Vinca alkaloids antitumor agent is a class of effective broad-spectrum antitumor agent, which is important and widely used in the clinic treatment of various cancers, such as leukaemia, lymphoma, breast cancer, lung cancer, liver cancer and many other solid tumors. This class of antitumor agents mainly includes vinblastine (VLB), vincristine (VCR), vindesine (VDS) and vinorelbine (VNR). Similar to other cytotoxic antineoplastics, these antitumor agents, however, lack selectivity for tumor tissues and lead to a severe dose-dependent acute toxicity, which is represented clinically as nausea, emesis, alopecia, and blood vessel irritation. More severe are the inhibition of bone marrow and strong neurotoxicity, and repeated administration will lead to severe complications. The toxic side effect of vinca alkaloids antitumor agent greatly limits their clinic application in the long-term treatment for tumors.
One approach to significantly decrease toxicity of vinca alkaloids antitumor agent is to alter their tissue distribution and improve their selectivity for tumor tissues. The liposome preparation of vinca alkaloids antitumor agent could reduce the toxic side effect of the agent and increase their distribution in tumor tissues, so as to mitigate their dose-dependent acute toxicity. The liposome preparation has been approved for the clinic treatment of various types of cancer and a satisfying therapeutical effect has been achieved. Two liposomal products, amphotericin liposome and paclitaxel liposome, have been approved by China State Drug Administration. The liposome preparations of vinca alkaloids antitumor agent, however, also suffer from many disadvantages. For example, the medicament is encapsulated in inner water phase and released from the liposome quickly, which results in instability of the preparation. The minimal size of the liposome is 50 nm and the entry of the liposome into cells is completed via fusion and pinocytosis mechanisms. Thus, the cytotoxic effect of the medicament encapsulated in liposome is weaker than that of free medicament. The production process of the liposome is complicated and the complexing of several lipid components (at least two lipid components) is required, wherein special equipments and devices are required to control the particle size. In addition, flocculation occurs frequently during the storage.
In water, amphiphilic molecules will aggregate spontaneously to form micelle when the concentration of the molecules is beyond critical micelle concentration. Taking advantage of this property, medicament is encapsulated in the hydrophobic core of the micelle. Micellar preparations have been used in clinic treatment practice for a long time. For example, deoxycholate sodium was utilized to solubilize amphotericin B and the like. A paper titled with “polymer micelle: a novel drug carrier” by Kun etc., summarized the use of micelle as a drug carrier (Adv. Drug. Del. Rev., 21:107-116, 1976). Recently, as a targeting, long-circulating and sustained release drug carrier, polymer micelle has been paid a great attention and becomes a research focus in the drug delivery systems. Yokoyama et al employed polymers to encapsulate antitumor drug and investigated its activity against solid tumor and cytotoxicity as well as its long-circulating property in blood, wherein the polymers was capable of forming micelle (Cancer res. 51: 3229-3236(1991)). Lipids modified with PEG-phospholipid have been demonstrated to be characterized by their long circulation in animal and human body, and can be safely used in clinic treatment (Gregoriadis, G. TIBTECH, 13: 527-537, 1995). As a carrier for drugs with poor solubility, polyethylene glycol-phospholipid micelle has been comprehensively summarized by investigators (Torchilin, V. P. J. controlled Release, 73:137-172).
Polyethylene glycol (PEG) is a water-soluble polymer that is stable under physiological condition. Because the space structure of PEG is capable of preventing the approach of plasma proteins, PEG has been widely used to modify the properties of phospholipid and protein drugs. In nanoparticle delivery system, PEG is capable of forming a hydrophilic protection layer on the surface of particles to prevent the aggregation of the particles, avoiding being recognized and phagocytized by reticuloendothelial system in body, and extending the retention time of drugs in blood circulation, whereby a long circulation is achieved.
Nano-micelle prepared from a phospholipid derivatized with polyethylene glycol possesses advantages over other nanoparticles. Its size is small between 10 nm and 30 nm. The nano-micelle is a dynamically stable system, which avoids the disadvantage of other nanoparticle delivery system, i.e. easy to aggregate, and on the other hand reaches lesion sites more easily, whereby the drug distribution in the tumor tissue is increased.